Defining the impact of pre-existing memory T cells in human immunity

项目摘要 全球有1800多万人感染艾滋病毒，1040万人感染结核病， 仅一年就有超过2亿人感染疟疾。有一种严重的未得到满足的需求 针对这些感染的疫苗和使用小鼠模型的研究尚未产生有效的疫苗。这个 发展功能性记忆反应，使免疫系统能够迅速而有力地对 以前经验丰富的病原体是疫苗效力的最重要因素。定义 人类产生记忆T细胞反应的机制是发育所必需的 有效的疫苗。先前在实验室小鼠中的研究表明，初级T细胞对新的 抗原来源于幼稚的T细胞。然而，在特定的无病原体条件下维持的小鼠是 在微生物暴露的程度上与人类有很大的不同。我们的实验室是第一个描述这一点的 人类成年人具有预先存在的针对病毒抗原的记忆表型(TMP)CD4+T细胞 他们从来没有被曝光过。我们进一步证明，近四分之一的艾滋病毒反应性T细胞 从未感染的人身上分离的克隆也对无关的微生物多肽产生反应，这表明这些TMP 细胞对许多不同的抗原有广泛的交叉反应。TMPS的发展可能反映了 胸腺发育后对环境抗原的累积暴露，这些细胞可能是 在初次感染期间最早做出反应的细胞。在这里，我们将在这些基础上使用黄色 以发热病毒(YFV)疫苗接种为模型来检验预先准备好的TMP细胞产生效力的假设 并优先在人类中产生接种后的记忆T细胞。我们将使用 一种称为四聚体的特殊细胞标记试剂，用于标记在接种前识别YFV抗原的T细胞和 在接种疫苗后多次使用。这将使我们能够在体外直接追踪YFV反应的T细胞，因为它们 在接种疫苗后进化。具体来说，我们将解决以下问题：(1)TMP细胞是否具有 与经典的记忆T细胞相比，更大的功能多样性和可塑性；(2)丰度或 TMP细胞的组成预测效应反应的速度和大小；(3)TMP细胞 优先产生接种后的记忆T细胞？这项研究将揭示Pre是如何 在疫苗接种中，现有的记忆前体细胞影响着CD4+T细胞免疫的效力和持久性。 了解环境条件如何影响人类T细胞库的后续反应 超越了疫苗效力，与人类健康的许多领域广泛相关，包括感染， 自身免疫力和癌症监测

Project Summary Globally, more than 18 million people are infected with HIV, 10.4 million people are infected with tuberculosis, and over 200 million people become infected by malaria in a single year. There is a critical unmet need for vaccines against these infections and studies using mouse models have not yielded effective vaccines. The development of a functional memory response that enables the immune system to react quickly and robustly to previously experienced pathogens is the single most important factor for vaccine efficacy. Defining the mechanisms by which memory T cell responses are generated in humans is essential for developing efficacious vaccines. Previous studies in laboratory mice have shown that primary T cell responses to novel antigens originate from naïve T cells. However, mice maintained under specific pathogen-free conditions are vastly different from humans in the extent of their microbial exposure. Our lab was the first to describe that human adults possess pre-existing memory phenotype (TMP) CD4+ T cells specific for viral antigens to which they have never been exposed. We further demonstrated that nearly a quarter of HIV-reactive T cell clones isolated from uninfected people also respond to unrelated microbial peptides, suggesting that these TMP cells are broadly cross-reactive to many different antigens. The development of TMPs likely reflects the cumulative exposure to environmental antigens following thymic development and these cells may be the earliest cells to respond during a primary infection. Here, we will build on these foundations and use yellow fever virus (YFV) vaccination as a model to test the hypothesis that pre-primed TMP cells generate potent effectors and preferentially give rise to post-vaccination memory T cells in humans. We will use a specific cell-labeling reagent called tetramers to tag T cells that recognize YFV antigens before vaccination and at multiple times after vaccination. This will allow us to trace YFV-reactive T cells directly ex vivo as they evolve following vaccination. Specifically, we will address the following questions: (1) does TMP cells have a greater functional diversity and plasticity compared to classic memory T cells; (2) does the abundance or the composition of TMP cells predict the rate and the magnitude of the effector response; (3) does TMP cells preferentially give rise to post-vaccination memory T cells? This study will reveal basic paradigms of how pre- existing memory precursors impact the potency and durability of CD4+ T cell immunity in vaccination. Understanding how the environment conditions the human T cell repertoire to influence later responses extends beyond vaccine efficacy and is broadly relevant to many areas of human health, including infection, autoimmunity, and cancer surveillance